The Diagnostic Role of Pharmacological Provocation Testing in Cardiac Electrophysiology

Authors, Journal, Affiliations, Type, DOI

• Chair: Elijah R. Behr (City St George's, University of London; St George's University Hospitals NHS)
• Co-Chair: Jacob Tfelt-Hansen (Copenhagen University Hospital Rigshospitalet)
• First authors: Bo Gregers Winkel, Bode Ensam
• Multi-society authors: representing EHRA, EAPCI, ESC Working Group on Cardiovascular Pharmacotherapy, AEPC, PACES, HRS, APHRS, LAHRS
• Journal: Europace, 2025; 27: euaf067
• Type: Clinical Consensus Statement (EHRA-led, multi-society endorsed)
• DOI: https://doi.org/10.1093/europace/euaf067

Overview

This 2025 EHRA-led multi-society clinical consensus statement addresses the diagnostic role of pharmacological provocation testing in cardiac electrophysiology, providing detailed practical guidance that the 2022 ESC VA/SCD guidelines did not fully specify. The statement covers sodium channel blocker (SCB) testing for Brugada syndrome, epinephrine/isoproterenol testing for CPVT and ARVC, adenosine testing for SVT/WPW, and acetylcholine/ergonovine testing for coronary artery spasm in cardiac arrest survivors. Advice statements requiring >90% or >70% expert agreement provide clear indications, contraindications, and clinical scenarios for each test. A key theme is the limitation of specificity of SCB testing and the polygenic basis of positive responses, which directly impacts family screening and diagnostic interpretation.

Keywords

drug challenge, provocation testing, sodium channel blocker test, ajmaline, flecainide, procainamide, pilsicainide, epinephrine, isoproterenol, adenosine, ergonovine, acetylcholine, sudden cardiac death, cardiac arrest, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, Wolff-Parkinson-White syndrome, coronary vasospasm, sudden arrhythmic death syndrome

Key Takeaways

Generic Advice

• Evaluate appropriateness (including relative contraindications) before every provocation test; contact an experienced centre if uncertain
• Informed consent must cover: indication, risks, benefits of positive/negative result, and potential side effects
• All tests must be performed in-hospital with advanced life support, defibrillator, and resuscitation personnel immediately available

Sodium Channel Blocker (SCB) Testing — Literature Evidence

• The proportion of patients with a type 1 Brugada pattern after SCB testing varies widely (4–60%) depending on cohort and agent
• False-positive rates with ajmaline: 16% in ARVC patients, 18% in myotonic dystrophy, 27% in AVNRT patients, 4.5% in healthy Caucasian controls — specificity is a major concern
• Ajmaline consistently induces type 1 Brugada pattern at higher rates than all other SCB agents; flecainide and procainamide are less potent
• The Shanghai consensus statement has downgraded drug-induced type 1 pattern from diagnostic to non-diagnostic for BrS in isolation; additional clinical, family, or genetic evidence is required for definite BrS
• SCN5A P/LP variants found in only ~20% of BrS cases; polygenic risk scores (common SNPs) associate with ajmaline positivity — positive SCB test may reflect polygenic susceptibility rather than monogenic BrS
• Ambulatory high precordial ECG monitoring detects spontaneous type 1 pattern in 13–34% of patients with prior drug-induced type 1 only

SCB Testing — Methods and Safety

• Agents: Ajmaline (class 1A; t½ ~5 min; max 1 mg/kg or 100 mg over 5–10 min) — preferred when available; flecainide (1C; t½ 13–16 h; max 2 mg/kg or 150 mg); pilsicainide (1C; t½ 3–6 h; mainly Japan); procainamide (1A; t½ 3–5 h; max 15–18 mg/kg or 1000 mg)
• Ajmaline preferred over flecainide when available (short half-life → better safety profile, more potent → higher sensitivity)
• High precordial lead positions (V1/V2 in 2nd/3rd intercostal spaces) required; increases sensitivity without altering specificity
• Stopping criteria (>90% consensus): (1) maximum dose administered; (2) type 1 Brugada pattern achieved; (3) QRS widening ≥30% from baseline; (4) ventricular arrhythmia beyond isolated PVCs; (5) profound bradycardia/sinus arrest; (6) Type II second-degree or third-degree heart block; (7) allergic reaction
• Absolute contraindications: type 2/3 second-degree or third-degree heart block, severe sinus node dysfunction, significant structural heart disease, active fever
• For patients with pre-existing AV conduction disturbances or SCN5A P/LP variants, perform test in cardiac catheterization laboratory with temporary pacing available
• Isoproterenol must be immediately available to treat ventricular arrhythmias
• After the test, monitor until QRS/PR return to baseline; minimum 1 hour observation

SCB Testing — Interpretation

• Positive result requires: type 1 Brugada pattern = J-point elevation ≥0.2 mV with coved ST elevation and T-wave inversion in ≥1 right precordial lead (V1 or V2, standard or high precordial position)
• J-point timing is best measured in a limb lead (or lateral chest lead if unavailable)
• Coved ST must continuously descend without concavity into negative T wave; at least 2 beats must fulfil criteria

SCB Testing — Clinical Scenarios (When to Do)

• Unexplained cardiac arrest (VF/polymorphic VT): Advised after comprehensive evaluation excludes alternative causes (ECG, echo, coronary assessment, cardiac MRI)
• First-degree relatives of SCN5A-negative definite BrS: SCB testing advised
• SCN5A variant of uncertain significance + symptoms/family history: Testing to aid segregation analysis
• Type 2/3 Brugada ECG pattern + cardiac syncope: Advised
• SADS relatives: Testing advised when death circumstances are suggestive of BrS (sleep/fever/suspicious ECG in decedent); testing may be appropriate more broadly in first-degree relatives after comprehensive evaluation

SCB Testing — When NOT to Do

• Already documented type 1 Brugada pattern (except if phenocopy suspected or substrate ablation planned)
• Asymptomatic subjects with incidental type 2/3 pattern and no other supporting features — routine testing not advised
• SCN5A P/LP variant carriers — only in expert centres with clear clinical rationale (e.g., VUS assessment, complex overlap syndrome)
• Asymptomatic first-degree relative of a patient with only drug-induced or fever-induced type 1 BrS without other features — clinical utility uncertain

SCB Testing — Paediatric Considerations

• Symptomatic children (arrhythmic syncope, febrile arrhythmic syncope, refractory febrile seizures with abnormal ECG) should undergo SCB testing at any age if needed
• Asymptomatic paediatric relatives: testing should be delayed until after puberty unless symptoms/ECG changes evolve
• Negative ajmaline test before puberty may turn positive after puberty (>16 years); repeat testing appropriate
• Paediatric electrophysiologist must decide indication; paediatric ICU bed required as precaution

Epinephrine Testing

• CPVT: Epinephrine challenge is appropriate only when exercise ECG test is not feasible
• Positive test for CPVT: >10 PVCs/min, 3 consecutive PVCs, recurrent couplets, bidirectional VT — bidirectional VT is most specific for underlying RYR2 P/LP variant
• LQTS: Not recommended (2022 ESC VA SCD guidelines did not recommend; expert group agreed)
• ARVC: Isoproterenol infusion (45 µg/min × 3 min) — uncertain additional value over 2010 Task Force Criteria; positive = polymorphic PVCs >3 morphologies + couplets, or LBBB-pattern VT not typical for RVOT-VT; 6 patients with positive isoproterenol challenge fulfilled definite ARVC at later follow-up (Denis series)
• Two protocols: Mayo (progressive, 0.025 → 0.20 µg/kg/min) and Shimizu (bolus 0.10 µg/kg then infusion)

Adenosine Testing

• Indications: Haemodynamically stable SVT or wide QRS tachycardia for differential diagnosis; sinus rhythm with minimally pre-excited ECG or documented SVT to unmask accessory pathway
• Mechanism: AV node blockade; reveals pre-excitation in WPW; terminates AVNRT/AVRT
• Contraindicated in: AF with WPW or irregular wide QRS tachycardia (risk of VF); haemodynamically unstable arrhythmias; severe aortic stenosis/LVOTO; LQTS with QT prolongation
• Max bolus dose up to 24 mg; 12 mg superior to 6 mg (91% vs 62% SVT termination rate)

Coronary Artery Spasm (CAS) Testing

• Indication: Cardiac arrest survivor with suspected CAS (chest pain history, exertional circumstances, normal other workup)
• Preferred agent: Intracoronary acetylcholine (escalating doses: 2 → 20 → 50/100 µg per artery)
• COVADIS diagnostic criteria: Reproduction of chest pain AND ischaemic ECG changes AND ≥90% epicardial vasoconstriction with flow limitation
• Safety: 0% mortality in recent studies; arrhythmias in <4% AF, <2% VT/VF, 0.1% SCA — events more common during right coronary testing
• Absolute contraindications: haemodynamic instability, early acute MI, heart block, NYHA III/IV HF, left main stenosis >50%, three-vessel obstructive CAD
• Intracoronary nitrates (200–400 µg GTN/ISDN) promptly relieve spasm
• Treatment if CAS confirmed: calcium channel blockers significantly reduce recurrent life-threatening arrhythmias

Provocation Testing in Pregnancy/Lactation

• Postpone all provocation testing until after delivery unless critical for management
• Postpone until after lactation unless critical for management
• Adenosine and agents with very short half-life (epinephrine, isoproterenol) may be used when necessary during lactation
• Ergonovine is contraindicated in pregnancy
• Ajmaline, flecainide, pilsicainide, procainamide: avoid unless strictly necessary; limited human data for fetal safety

Limitations of the Document

• Not a full systematic review with graded levels of evidence; consensus statements based on ≥70% or ≥90% expert agreement
• Limited evidence comparing SCB agents head-to-head; no gold standard to calculate true sensitivity/specificity
• Paediatric data for most tests are sparse, especially for adenosine, ergonovine, and acetylcholine
• Data on CAS testing in all unexplained cardiac arrest survivors (not just those with clinical CAS features) remain uncertain

Key Concepts Mentioned

• concepts/Pharmacological-Provocation-Testing — primary concept; detailed guidance on all provocation tests
• concepts/Shanghai-Score-System — drug-induced type 1 downgraded; definite BrS requires additional evidence
• concepts/Coronary-Vasospasm — COVADIS criteria; acetylcholine protocol

Key Entities Mentioned

• entities/Brugada-Syndrome — primary focus; SCB testing indications/contraindications/clinical scenarios
• entities/CPVT — epinephrine testing guidance; EST preferred over epinephrine
• entities/ARVC — isoproterenol testing; 16% ajmaline false-positive rate
• entities/Long-QT-Syndrome — epinephrine testing no longer recommended
• entities/SCN5A — P/LP variant carriers should generally not undergo SCB testing

Wiki Pages Updated

• wiki/sources/pharmacological-provocation-europace-2025.md — created (this file)
• wiki/concepts/Pharmacological-Provocation-Testing.md — created (new)
• wiki/entities/Brugada-Syndrome.md — updated: SCB testing protocol section, clinical scenarios, indications/contraindications
• wiki/entities/CPVT.md — updated: epinephrine testing context
• wiki/entities/ARVC.md — updated: isoproterenol testing, false-positive rate
• wiki/concepts/Coronary-Vasospasm.md — updated: acetylcholine protocol, COVADIS criteria, CAS in cardiac arrest
• wiki/concepts/Shanghai-Score-System.md — updated: 2025 consensus on drug-induced type 1 interpretation
• wiki/sourceindex.md — updated
• wiki/wikiindex.md — updated